Mechanism of cytokine inhibition of beta-adrenergic agonist stimulation of cyclic AMP in rat cardiac myocytes. Impairment of signal transduction.

Abstract

Studies conducted in our laboratory have demonstrated that activated immune cells produce a soluble inhibitor(s) of cardiac myocyte contractile and cyclic AMP (cAMP) responses to beta-adrenergic stimulation. To examine the mechanism of this effect, metabolic assays were conducted on cultured rat cardiac myocytes incubated in the presence and absence of supernatants harvested from rat activated splenocyte cultures. Intracellular cAMP accumulation in response to isoproterenol was inhibited by up to 74% in a dose-dependent fashion by conditioned media containing soluble cytokines from activated immune cells. By use of myocyte cultures in which contaminating nonmyocyte proliferation was inhibited by nonlethal irradiation, this phenomenon was shown to be independent of mitogenic effects. Isobutylmethylxanthine, a phosphodiesterase inhibitor, did not ablate cytokine-induced inhibition of cAMP accumulation. Parameters of beta-adrenergic receptor binding and affinity were also unaffected. cAMP suppression was maintained after cholera toxin stimulation of cAMP production via stimulatory G protein ADP-ribosylation. cAMP inhibition was not apparent when cells were stimulated with forskolin, a direct adenylate cyclase activator. Importantly, pertussis toxin treatment significantly ablated cytokine-induced cAMP inhibition. Thus, interference with agonist-occupied beta-adrenergic receptor coupling to adenylate cyclase to produce cAMP and subsequent contractile responses is induced by a factor(s) elaborated by activated immune cells. This interference occurs at the level of signal transduction across the membrane, can be overridden by pertussis toxin, and may involve changes in the coupling of the stimulatory/inhibitory G proteins to adenylate cyclase. These results demonstrate a novel mechanism of cytokine-induced myocyte dysfunction and may have important pathophysiological ramifications in immune-mediated myocardial diseases.

Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction

“…22,23 Indirect myocardial depression via upregulation of the inducible form of nitric oxide synthase 24,25 can in turn induce desensitization of myofilaments to intracellular calcium, 26 as well as modulate the contractile response to adrenergic stimulation. 27 These may be initially protective mechanisms attempting to decrease the amount of mechanical work output by the heart during acute MI. However, chronically this could increase wall stress, leading to further TNF-␣ production and secondary matrix and myocyte remodeling and aggravated mechanical dysfunction.…”

CXCR4 modulates contractility in adult cardiac myocytes

“…Sepsis-associated cardiac dysfunction was thought to be mediated, in part, by circulating or "humoral" myocardial depressants that were subsequently identified as predominantly inflammatory cytokines (including tumor necrosis factor-1alpha (TNF-1α), interleukin-1beta, (IL-1β) [25], IL-6 [26], IL-2 [27] and interferon-gamma (IFN-γ)). These ideas were supported by numerous animal [28][29][30] and by in vitro studies [25,31,32]. However, clinical trials (reviewed by Anker et al [33]), that used "targeted" approaches to neutralize cytokines, such as TNF, were unsuccessful in treating patients with moderate to advanced heart failure.…”

Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms

“…Additionally, LPS exposure increased both nitrite production in myocytes and cGMP formation in reporter fibroblasts, suggesting a possible cGMP-mediated mechanism for NOinduced negative inotropy. Another experiment by Chung et al implicated inhibition of the adenylyl cyclase/cAMP second messenger system as the explanation for reduced contractility in the presence of NO [15]. Peroxynitrite, a product of interaction between NO and the superoxide anion, has also been proposed as a possible cardiodepressant [2,16].…”